The proposed K01 project was designed to test important hypotheses while creating an opportunity to increase the candidate's research skills in focal training areas. Dr. Iatridis proposes an intensive training program overseen by an Advisory Board to allow him to progress from mentored to independent scientist. His Advisory Board is comprised of members who are well-recognized for their contributions to biomechanical, computational, and biochemical research on the spine and intervertebral disc. Along with regular meetings with mentors, course work, and seminars, Dr. Iatridis will participate in extended training programs in biochemistry and molecular biology, computational modeling, and magnetic resonance imaging which address specific hypotheses of his research plan and increase his skill base. The long-term goal of the research plan is to isolate mechanical factors that lead to degenerative disc disease and spine pathology. The primary objective of the proposed research is to investigate the effect of mechanical loading conditions applied to the intervertebral disc on the physical signals that cuase a biosynthetic response from the cells and tissue remodeling. Specific aims were developed that are consistent with several future directions for research recommended by the 1995 NIH/AAOS workshop on low back pain and NIH PA97-058. A general hypothetical model is introduced where the intervertebral joint forces are related to dominant load carriage mechanics in the disc tissue and those physical signals that cause a biosynthetic response. The hypotheses test the influence of specific joint forces on on observed intervertebral disc remodeling. External fixators allow precise control over the joint forces applied to a rat tail in vivo. The tail will chronically be exposed to immobilization, low-force compression, high-force compression, and shear loading, as well as loading followed by removal of the fixators to probe for recovery (independent variables). Dependent variables describing the composition and biosynthetic response of the disc tissue will be measured using biochemical, in situ hybridization, and MRI techniques. The mechanical and electrochemical fields in the disc tissue will be calculated using a poroelastic and chemical electric finite element model and mechanical properties measured in this study as input parameters. The biosynthetic response of the disc will be compared to the dominant load carriage mechanisms in the disc tissue in a site-specific manner. This combined experimental and theoretical project provides a framework for future developments on the cell scale by investigating cellular transduction mechanisms, and on the full joint scale by isolating joint forces that may acccelerate intervertebral disc degeneration in human spines.